Method of using focused acoustic waves to deliver a pharmaceutical product

ABSTRACT

An improved method and apparatus for delivering medication to the lungs is described. Acoustic ink printing technology is modified to operate as an inhaler that generates tiny droplets near a patient&#39;s nose or mouth. The tiny droplets are easily carried by air currents into the patient&#39;s lungs. The inhaler itself is preferably a battery operated portable device that can be easily carried and easily cleaned to avoid contaminating the medication.

BACKGROUND OF THE INVENTION

[0001] Many pharmaceutical products or drugs that provide relief fromnasal or lung ailments are delivered through the respiratory system. Inorder to deliver these drugs, typically, the drug is compressed in acontainer. Users release the compressed pharmaceutical by opening avalve for a brief interval of time near the user's mouth or nose. Pumpmechanisms may also be used to directly spray the pharmaceutical intothe user's mouth or nose. The user may then draw a breath to furtherinhale the pharmaceutical product.

[0002] These techniques for delivering pharmaceuticals pose severalproblems. The first problem is that the droplet size produced istypically too large to be carried in an air stream generated by a normalintake of breath. Thus, in order to transport the larger droplets ofpharmaceutical products, the product is propelled into the orifice. Thismay be done by using compressed air or by expelling the pharmaceuticalproduct into the orifice at a high speed.

[0003] Unfortunately, a fast moving particle, defined as a particle thatis moving much faster than the accompanying airstream, cannot easilytravel around bends that occur in the human respiratory system. Thus,when the traditional means of injecting pharmaceuticals into the mouthare used, much of the pharmaceutical product is deposited on the back ofthe mouth or in the throat. The deposited pharmaceutical product maythen be ingested into the digestive tract instead of the respiratorysystem. The ingested pharmaceutical product represents lost or wastedmedication.

[0004] A second problem is that the varying amounts of lostpharmaceutical product makes it difficult to control dosages. Wasteddroplets of medication that are deposited on the back of the throatmakes it possible that the patient will receive insufficient medication.Determining the amount wasted and trying to compensate for the wastedmedication is a difficult and inexact process.

[0005] Thus an improved method and apparatus of deliveringpharmaceutical products to a patient's respiratory system is needed.

SUMMARY OF THE INVENTION

[0006] In order to more efficiently deliver pharmaceutical products,acoustic ink printing (AIP) technology has been adapted for use indelivering medications to a patient. In one embodiment of the invention,a liquid medication is distributed over several acoustic ejectordrivers. The drivers are inserted into or placed in close proximity toan orifice of the patient such as the mouth or the nose. A power sourceprovides energy to each driver. The drivers convert the energy intofocused acoustic waves that cause small droplets of medication to beejected into the orifice. Air currents distribute the medicationthroughout the patient's respiratory system.

BRIEF DESCRIPTION OF THE DRAWINGS.

[0007]FIG. 1 shows a cross section of a droplet ejector in an array ofdroplet ejectors ejecting a droplet of pharmaceutical product.

[0008]FIG. 2 shows ejection of droplets using capillary action.

[0009]FIG. 3 shows one embodiment of forming an inhaler that uses asingle transducer to drive multiple droplet sources.

[0010]FIG. 4 shows an example distribution of droplet ejectors on aninhaler head.

[0011]FIG. 5 shows a cross sectional side view of one embodiment of aninhaler designed for insertion into the mouth of a patient.

[0012]FIG. 6 shows the inhaler in use by a patient.

DETAILED DESCRIPTION OF THE INVENTION

[0013] An inhaler system that adapts acoustic ink printing technology tooutput small droplets of pharmaceutical product at a low velocity isdescribed. The droplets are preferably less than 10 micrometers indiameter. Small droplet size and an output speed approximately matchingthe rate of airflow into the respiratory system maximizes the quantityof medication administered to a patient's lungs.

[0014]FIG. 1 shows an array 160 of droplet sources such as dropletsources 100, 101, 102, 103 for use in an inhaler 144. Each dropletsource 100, 101, 102, 103 is capable of outputting droplets ofpharmaceutical product. Inhaler 144 is designed such that the combinedoutput of all droplets sources in array 160 over a predetermined periodof time are sufficient to deliver a desired volume of pharmaceuticalproduct to a patient. The pharmaceutical product is typically liquidthat contains organic compounds for deposition in the lungs of thepatient.

[0015]FIG. 1 includes a cross sectional view of one example dropletsource 100 in array 160. The cross sectional view also shows adistribution of a reservoir of pharmaceutical product 108 shortly afterejection of a droplet 104 and before a mound 112 on a free surface 116has relaxed. A radio frequency (RF) source 120 provides a RF driveenergy to a driver element such as a transducer, typically apiezo-electric transducer 124, via bottom electrode 128 and topelectrode 132. The acoustic energy from the transducer passes throughbase 136 into an acoustic lens 140. Acoustic lens 140 focuses thereceived acoustic energy into a focused acoustic beam 138 thatterminates in a small focal area near free surface 116. In theillustrated embodiment, each droplet source in array 160 of dropletsources includes a corresponding acoustic lens and transducer to form anarray of acoustic lenses and transducers.

[0016] Traditional acoustic ink printers usually use RF drives withfrequencies of around 100 to 200 Megahertz (MHz). However, when dropletsources are used in inhalers, higher frequencies are preferred becausehigher frequencies generate smaller droplets that are more easilycarried by air currents into the respiratory tract. Droplet sizes aretypically on the order of the wavelength of the bulk acoustic wavepropagating in the pharmaceutical product. This wavelength may bedetermined by dividing the velocity of sound for bulk wave propagationin the pharmaceutical product by the frequency of the bulk acousticwave. Thus by increasing frequency, droplet size can be reduced A RFdrive frequency exceeding 300 MHz typically results in the generation ofdroplets smaller than 5 micro-meters in diameter. Thus inhalers thatdirectly eject droplets preferably operate in frequency ranges exceeding300 MHz.

[0017] Higher frequencies used in inhaler droplet sources also result inhigher power losses. Power losses in a droplet source is approximatelyproportional to the square of the frequency. Power losses in a dropletsource are also proportional to the distance “d” from the top surface141 of acoustic lens 140 to free surface 116 of the pharmaceuticalproduct reservoir. In order to compensate for increased power losses dueto the increased operating frequencies, distance “d” may be reducedcompared to traditional AIP print heads. In inhaler applications, adistance “d” less than 150 micrometers may be used to conserve power.

[0018] A more detailed description of the droplet source or “dropletejector” operation in a traditional AIP printhead is provided in U.S.Pat. No. 5,565,113 by Hadimioglu et al. entitled “LithographicallyDefined Ejection Units” issued Oct. 15, 1996 and hereby incorporated byreference.

[0019]FIG. 1 uses focused acoustic energy to directly eject a droplet.FIG. 2 shows an alternative method of generating droplets usingcapillary action. When generating capillary wave-driven droplets, theprinciple mound 204 does not receive enough energy to eject a droplet.Instead, as the principle mound 204 decreases in size, the excess liquidis absorbed by surrounding capillary wave crests or side mounds 208,212, 216, 220. These wave crests eject a mist corresponding to droplets224, 228, 232, 236. In order to generate capillary action dropletsinstead of focused, single ejection droplets, each ejector transducergenerates shorter pulse widths at a higher peak power. Example pulsewidths are on the order of 5 microseconds or less when the transducerprovides a peak power of approximately one watt or higher per ejector.

[0020] One advantage of using capillary action is the lower frequenciesthat can be used to create smaller droplets. The diameter of capillarygenerated droplets are similar in magnitude to the wavelength ofcapillary waves. The wavelength of capillary waves can be determinedfrom the equation: wavelength=[2*Pi*T/(ro*f^ 2)]^ (⅓) wherein T is thesurface tension of the pharmaceutical fluid, ro is the density of thepharmaceutical fluid and f is the frequency output of the transducer.This equation and a more detailed explanation is provided on page 328 ofEisenmenger, Acoustica, 1959 which is hereby incorporated by reference.At typical densities and surface tensions, frequencies of 10 Megahertz(MHz) generate a capillary wavelength of 1.5 micrometers and a frequencyof 1 MHz generates a capillary wavelength of 6.8 micrometers. Thus it ispossible to generate approximately 5 micrometer diameter droplets at RFfrequencies about two orders of magnitude smaller than the bulk wavesused to generate “conventional” AIP droplets.

[0021] In capillary wave droplet systems, the lower frequencies usedallows more flexibility in materials and tolerances used to fabricatetransducers and acoustic lenses used to form the array of dropletsources. For example, plastics are not as lossy at the lowerfrequencies. The lower loss levels allow relatively inexpensive moldedplastic spherical lenses to be used as acoustic lenses.

[0022] A second method of minimizing the cost of fabricating an array ofdroplet sources is to replace the plurality of transducers with a singletransducer, the energy from the single transducer distributed tomultiple lenses corresponding to multiple droplet sources. FIG. 3 showsan example of such a single transducer structure. In FIG. 3, eachdroplet source corresponds to an acoustic lens such as acoustic lenses308, 312, 316. The acoustic lenses are positioned over a single largetransducer 304. Each acoustic lens independently focuses a portion ofthe bulk planar wave produced by single large transducer 304 to createdroplets across a free surface 320. Using a single transducer instead ofthe multiple transducers shown in FIG. 1 substantially reduces the costassociated with multiple transducers and the electronics to drivemultiple transducers.

[0023] The number of droplet sources in an array of droplet sources mayvary and typically depends on the dosages that will be administered. Atypical five micron diameter drop of pharmaceutical product containsabout 0.07 picoliters of fluid. Assuming a repetition rate of 200 KHz, arate easily achievable with the typical ejector, each droplet sourcewill deliver approximately 14 microliters per second. To administermedication at the rate of 100 milliliters per second, a typical numberof ejectors may be around 7,000.

[0024]FIG. 4 shows a top view 404 of an example distribution of dropletsources 408. Typically, the droplet sources are mounted on a circularhead 412 over a distance of approximately 10 centimeters to facilitateinsertion into an oral cavity. Alternative configurations of dropletsources may be designed for insertion into a nasal cavity. Although acircular pattern of droplet sources best utilizes the surface area ofcircular head 412, in high viscosity pharmaceutical products, the flowof the product evenly across a circular pattern may prove difficult.Thus, in an alternate embodiment, a more linear pattern of dropletsources may be used.

[0025] Prevention of contamination, both from airborne particulatematter as well as organic matter such as bacteria is an importantconcern with the inhaler. Typically, openings 414 in circular head 412are substantially larger than the droplet size ejected. For example, atypical opening size for ejection of a 10 micron diameter droplet may beapproximately 100 microns. When droplet sources are not activated, thepharmaceutical product is maintained within the circular head 412 viasurface tension across opening 414. The relatively large exposed surfacearea of opening 414 may allows dust and other particulate matter toenter the openings and contaminate the pharmaceutical product.

[0026] A cover 413 that fits over the circular head 412 helps minimizeparticulate contamination. In one embodiment opening and closing cover413 may switch on and off the inhaler. An alternate method of avoidingcontamination uses micro electro-mechanical structure (MEMS) covers 416positioned over each opening. MEMS cover 416 may open for a short timeinterval allowing droplets to be ejected and remain closed during othertime periods. In one embodiment, the cover, whether a large area coveror a MEMS covers, may be electronically controlled such that theejection of droplets causes the cover to automatically retract out ofthe path of the ejected droplets. Such electronic control may beachieved by synchronizing a cover control with the electrical impulsedriving the transducers.

[0027] Besides particulate contamination, bacterial contamination shouldalso be minimized. One method of controlling bacterial contamination isto regularly sterilize the ejector head using UV radiation. However, maypatients do not have the discipline to regularly sterilize the ejectorhead. One method of forcing a regular sterilization schedule is toautomatically expose the ejector heads to UV radiation whenever theinhaler power supply is being recharged.

[0028] Often, even with sterilization and covers, some contamination ofthe ejector heads over time is inevitable. Furthermore, when fresnelzone plates are used as acoustic lenses, the ejector may be hard toclean making it difficult to use the same ejector head with severaldifferent medications. Plastic spherical lenses are easier to clean andcan be used at lower frequencies, such as is typically associated with acapillary action droplet ejector. In systems where several differentmedications are being administered or where the ejector becomesotherwise contaminated, the ejector head 420 detaches from a body of theinhaler and can be replaced by a replacement head or a disposableejector head. A clip-on or other fastener mechanism attaches ejectorhead 420 to the body. In one embodiment of the invention, an ultraviolet(UV) radiation source sterilizes ejector head 420.

[0029]FIG. 5 shows a cut away side view of one embodiment of inhaler 500including ejector head 504 and body 508. Electrical conductors 512connect each piezoelectric element 516 in ejector head 504 to a powersource 520 when a switch 524 is closed. The power source may be abattery such as an alkaline or nickel/cadmium battery.

[0030] A typical ejector uses approximately two nanojoules of acousticenergy at the liquid surface per drop of liquid ejected. Multiplying thepower needed at the liquid surface by the loss factor of the ejectorresults in an approximate power requirement of 20 nanojoules per ejectorat the ejector head. The total power used is calculated by multiplyingthe power per ejector at the ejector head by the total number ofejectors. To deliver a 100 microliter dose five times a day, the totalpower requirement is approximately 140 joules which is well within thepower capabilities of most batteries, including most rechargeablenickel/cadmium batteries.

[0031] In one embodiment of the invention, a handle 527 of the AIPinhaler includes a container that stores a reservoir 525 of medication.When the ejector head is attached to the inhaler body, a pipe 529,typically a hypodermic needle punctures a seal 531 that seals thereservoir 525 of medication. Typically, seal 531 is a rubber gasket thatcovers a section of the container of medication. A second pressurizationneedle 533 also punctures the rubber gasket and pumps gas into reservoir525 slightly pressurizing the medication. The applied pressure should besufficient to force the medication up pipe 529; however, the pressureshould not be excessive such that it breaks the surface tension at theopenings of the ejector head. Breaking the surface tension willprematurely force medication from the openings of the ejector head.Pressure detection system 535 monitors the pressure differential betweenthe ambient surroundings and the pressure inside reservoir 525 andmaintains the desired pressure to keep fluid in the ejector head withoutbreaking the surface tension of each opening.

[0032] When drops are to be ejected, ejection switch 524 is closed.Closing ejection switch 524 activates the ejectors on ejector head 504for a predetermined time interval. In one embodiment the invention,switch 524 is a trigger 526. After the droplet ejectors are placed inclose proximity to an oral cavity, a patient presses trigger 526 closingof switch 524. Closing switch 524 cause the ejection of medication. In asecond implementation of a switch control, an airspeed detector 527controls the closing of switch 524. In particular, when an inhalation bythe patient causes the speed of air around the ejectors to approximatelymatch the expected speed of ejected droplets, the airspeed detectorcloses switch 524. The matched air speed provides an optimal air currentfor carrying droplets from the ejector into a patient's lungs.

[0033] Dosage setting switch 528 allows the user to adjust the dosage ofmedication provided by adjusting the duration of ejector operation afterswitch 524 is closed. In the illustrated embodiment, dosage settingswitch 528 controls timer 532. Timer 532 determines a time duration overwhich power is provided to piezoelectric 516. The time interval istypically proportional to the dosage set on dosage setting switch 528.When all ejectors are fired, the time interval is typically the dosagedivided by the total output of ejectors on ejector head 504 per unittime.

[0034] When small dosages are desired, the dosage setting switch 528 maybe programmed to reduce the number of ejectors fired on ejector head 504by adjusting a control signal. The control signal switches ejectors indrive circuit 536. Reducing the number of ejectors fired reduces theoutput of pharmaceutical product per unit time. The duration of ejectorfiring may also be selected based on the droplet ejector switchingmechanism. When an airspeed detector 527 is used, extension of thepharmaceutical discharge time may be undesirable. Instead, it may bedesirable to maximize the ejection of droplets during a very short timeinterval to take advantage of the optimal air speed, thus typically allejectors will fire for a fraction of a second. However, in trigger basedor manual operation, it may be desirable to extend the time intervalslightly to allow for imprecise synchronization between ejection ofdroplets and inhalation.

[0035] Drive circuit 536 provides the drive signal to the ejectors onejector head 504. In a simple implementation of drive circuit 536, allejectors are simultaneously activated. Thus, in one embodiment of theinvention, all ejectors may be connected in parallel such that closingswitch 524 results in simultaneous ejection of droplets from allejectors. However, circumstances may dictate that all ejectors not befired at once. For example, when power source 520 is low on energy andneeds recharging, the electric current provided may be insufficient tofire all ejectors simultaneously. In such cases, the drive circuit maydetect the lower power output and fire different ejectors at differenttimes or switch some ejectors off altogether with a correspondingincrease in time duration to allow dispensing of the recommended dosage.As previously described, a request for a very low dosage may also resultin firing of less than all of the ejectors at once. System design myalso dictate that not all ejectors are fired at once. Typically, RFpower is power is switched on to a group of ejectors for a timeduration, on the order of microseconds, and then switched off forseveral microseconds. In order to minimize the peak power requirementsof the inhale when the RF power is switched off to the group ofejectors, a second group of ejectors may receive RF power. Thus amultiplexing circuit may alternately switch groups of ejectors on andoff and avoid overlapping firing times.

[0036]FIG. 6 illustrates the use of the inhaler by a human subject. Inthe illustrated embodiment, the patient 600 inserts the applicator orejector head 604 of the inhaler 608 into an oral cavity 612. Afterinsertion of inhaler 608, a finger such as a pointer or trigger finger616 applies pressure to a switch 620. Alternately, the inhalation of aircauses an airspeed indicator to detect the airspeed in aperture 624 andtrigger a switch when the airspeed reaches a desired value. Under eitherimplementation, the switch closes at a particular point in time causingpower to be provided to the ejectors for a preset time duration and theejection of a mist of medication into oral cavity 612.

[0037] As the mist of medication is produced, the patient deeplyinhales. The inhalation causes air currents 628 to carry the droplets632 of pharmaceutical product to the patient's lungs 636 where thepharmaceutical product is absorbed. The matching of the ejection speedof droplets 632 with the speed of air currents 628 and the small size ofdroplets 632 maximizes the percentage of pharmaceutical product thatreaches lungs 636 and minimizes the percentage of pharmaceutical productdeposited on the back of the throat 640.

[0038] While the preceding invention has been described in terms of anumber of specific embodiments, it will be evident to those skilled inthe art that many alternatives, modifications and variations may beperformed while still remaining within the scope of the teachingscontained herein. For example, specific power consumption of ejectors,ejector arrangements, methods of switching on the ejectors and methodsof maintaining sterility of the inhaler have been described. However,such details should not be used to limit the scope of the invention andare merely provided to serve as examples for performing the claimedinvention and lend clarity to the description. Accordingly, the presentinvention should not be limited by the embodiments used to exemplify it,but rather should be considered to be within the spirit and scope of thefollowing claims and its equivalents, including all such alternative,modifications and variations.

1. A method of delivering pharmaceutical product comprising theoperations of: depositing a pharmaceutical product across a plurality ofdriver elements; positioning the plurality of driver elements withinfour inches of a human orifice; delivering electrical power to theplurality of driver elements causing the plurality of driver elements todeliver acoustic energy to the pharmaceutical product, the acousticenergy focused by acoustic lenses to cause ejection of droplets ofpharmaceutical product into the human orifice.
 2. The method of claim 1wherein the drive elements are piezo-electric transducers.
 3. The methodof claim 1 wherein all drive elements in the plurality of drive elementsare simultaneously provided with electrical energy to cause simultaneousejection of multiple droplets of pharmaceutical product.
 4. The methodof claim 1 wherein each drive element in the plurality of drive elementsis provided with electrical energy within a five second time interval tocause ejection of multiple droplets of pharmaceutical product over thefive second time interval.
 5. The method of claim 1 further comprisingthe operation of: focusing the acoustic energy from each driver using aplurality of acoustic lenses.
 6. The method of claim 5 wherein theacoustic lenses are fresnel lenses.
 7. The method of claim 5 wherein thelenses are spherical molded plastic lenses.
 8. The method of claim 7wherein the spherical molded plastic lenses are formed on a plasticsubstrate and the drivers are bonded to the plastic substrate.
 9. Themethod of claim 1 wherein the driver elements output RF energy.
 10. Themethod of claim 9 wherein the RF energy has a frequency higher than 300MHz in order to generate a droplet sizes smaller than 6 micrometers. 11.The method of claim 9 wherein the RF energy has a frequency lower than10 MHz.
 12. The method of claim 1 wherein the RF energy generatescapillary droplets of pharmaceutical product, each droplet having adiameter less than 10 micrometers.
 13. The method of claim 1 wherein theorifice is a mouth, the method further comprising the operation of.opening the mouth; and inserting the plurality of drive elements intothe mouth before delivering electrical power to the plurality of driveelements.
 14. The method of claim 1 wherein the orifice is a nostril ofa nose, the method further comprising the operation of: inserting theplurality of drive elements into the nose before delivering electricalpower to the plurality of drive elements.
 15. A method of deliveringpharmaceutical product comprising the operations of: distributing apharmaceutical product over a plurality of lenses; and focusing acousticenergy from the plurality of lenses to cause ejection of droplets ofpharmaceutical product.
 16. The method of claim 15 further comprisingthe operation of: detecting the velocity of ambient air; and causing theejection of droplets when the velocity of ambient air reaches a criticalair speed.
 17. The method of claim 15 wherein the focusing occurs for aperiod of less than five seconds to deliver a preset dosage ofpharmaceutical product.